Airway inflammation plays a critical role in the pathogenesis of chronic asthma. Glucocorticoid (GC)s are the cornerstone of anti-inflammatory therapy in this disease. However, not all asthmatics improve their pulmonary function following GC therapy. These patients are subjected to the unwanted side effects of prolonged systemic GC therapy, often in situations where there is no evidence that it is exerting any appreciable benefit. Recent analyses of the economic burden of asthma suggest that the costs of asthma are largely attributable to uncontrolled disease. Although patients with severe asthma represent a minority of asthmatics, they account for much of the morbidity and cost of the disease due to use of costly medications, emergency room visits and frequent hospitalizations. We have recently found that peripheral blood monocytes and BAL macrophages of corticosteroid-resistant asthmatics have increased baseline levels of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) activation in their monocyte/macrophages. The current proposal will examine the mechanisms underlying increased p-p38 MAPK and its role in posttranslational modifications of GCR alpha function in CR asthma. We hypothesize that p38 activation results in corticosteroid resistance by interfering with GCR alpha nuclear translocation required for optimal transactivation and transrepression. Preliminary data indicates that loss of asthma control is associated with the expansion of unique organisms not seen in the normal microbiome. Our specific aims will be: 1) to determine the role of p-p38 MAPK in monocyte/macrophage corticosteroid insensitivity; 2) to characterize the microbiome in asthmatics with persistent airway obstruction to determine the potential trigger for cell p38 activation in CR asthma; 3) to determine whether the clinical steroid sparing effects of vitamin D result from its ability to induce mitogen activated kinase phosphatase-1 (MKP-1), a critical phosphatase that downregulates p38 activation in monocytes/macrophages; 4) to examine the mechanisms leading to reduced half-life of MKP-1 in CR asthmatics. The elucidation of mechanisms underlying steroid resistance will have important consequences for development of biomarkers to diagnose and monitor steroid resistance, as well as develop novel therapeutic modalities in the treatment of CR asthma as well as other chronic inflammatory conditions where altered GC responsiveness contributes to persistent tissue inflammation.